The agouti peptide plays a central role in determining the type of melanin (eumelanins or phaeomelanins) produced within the melanocyte. The normal action of agouti is most likely as an antagonist of the MSH receptor, MC1-R. In the mouse, ectopic expression of agouti leads to obesity, potentially mediated through an interaction with (hypothalamic) MC4-R. The aims of the proposed project are: 1) To study the structure the agouti peptide to define the specificity of its effects on pigmentation and obesity; 2) to determine the binding site and mechanism of antagonism of melanocortin receptors; 3) to test the hypothesis that agouti may act independent of melanocortin receptor antagonism; 4) to identify other members of the agouti family that may be more relevant to endogenous antagonism of MC4-R; and, 5) to test the hypothesis that antagonism of MC4-R is responsible for agouti-mediated obesity.